Therapeutic PSA-targeted poxviral vaccines for prostate cancer have been well tolerated. Prostvac (PSA-TRICOM), a vaccine developed within the CCR, was evaluated for safety, prolongation of PFS, and OS in a randomized, controlled, double-blinded, multicenter phase II study with 125 patients. Eligible patients had minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Prostvac is composed of 2 recombinant viral vectors, each encoding transgenes for PSA and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). A vaccinia-based vector was used for priming, followed by 6 planned fowlpox-based vector boosts. Patients were allocated 2:1 to Prostvac + GM-CSF vs. control (empty vectors + saline). Two patients received PROSTVAC and 40 received the control. Patient characteristics were similar. The primary endpoint was PFS, which was similar in the two groups (P = 0.6). However, at 3 years post-study, Prostvac patients had a better OS, with 25/82 (30%) alive vs. 7/40 (17%) for control patients at time of analysis. Median survival was extended by 8.5 months (24.5 months for vaccine vs. 16 months controls; estimated hazard ratio 0.56 [95% CI 0.37-0.85], stratified log rank P = 0.0061). Prostvac immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of a clinically meaningful benefit, but need to be confirmed in a larger, ongoing phase III study. A concurrent randomized phase II trial employing a recombinant poxviral vaccine provided evidence of immune responses. This study employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Of 32 patients vaccinated, 12 showed declines in serum PSA; 2 of those 12 had evaluable decreases in index lesions. Median OS was 26.6 months compared with a nomogram-predicted OS of 17.5 months. Patients with greater PSA-specific T-cell responses showed a trend (P = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF vs. no GM-CSF. Patients with a nomogram-predicted survival greater than the median appeared benefit most from treatment, suggesting that using the vaccine earlier in the disease process may lead to substantially improved outcomes. A phase I study was conducted to determine the safety and feasibility of an intraprostatic PSA-based vaccine in men with prostate cancer and local failure following radiotherapy or cryotherapy or clinical progression on androgen-deprivation therapy in the absence of local definitive therapy. This study showed significant intratumoral infiltrates following vaccination. A manuscript on this study was recently published. A collaborative (GMB, UOB, LTIB) neoadjuvant study of s.c. PSA-TRICOM in men with localized prostate cancer prior to radical prostatectomy was recently initiated. A trial of PSA-TRICOM in the active surveillance setting has just opened in collaboration with the Division of Cancer Prevention, NCI. A randomized, double-blind, phase III efficacy trial of Prostvac in men with asymptomatic or minimally symptomatic mCRPC has recently completed accrual, based on the previously mentioned randomized phase II study. This study enrolled 1,298 men with prostate cancer in 215 centers across 15 countries. Dr. Gulley is the lead PI for this international study, which is expected to have completed enrollment in January 2015. The following collaborative vaccine clinical trials at the NIH Clinical Center are ongoing or recently completed. We recently published an open-label study to evaluate the safety and tolerability of Panvac with GM-CSF in patients with metastatic adenocarcinoma (GMB and LTIB). This includes a breast cancer patient who initially had a PR followed by a durable CR, on study for over 7 years. We also recently published a first-in-human open-label phase I study to evaluate the safety and tolerability of a vaccine (GI-6207) developed in the CCR consisting of whole, heat-killed recombinant Saccharomyces cerevisiae (yeast), genetically modified to express CEA protein, in adults with metastatic CEA-expressing carcinoma. Based on this trial, a phase II trial in medullary thyroid cancer has been initiated. A phase I dose-escalation study of yeast-brachyury (a CCR-developed vaccine) was recently completed. Brachyury expression is involved in drug resistance and EMT, and has other stem cell-like properties. Final results of this trial were recently presented at ASCO and a ms has been submitted. The results include good safety (no DLT), good immune response and a PR in a patient with chordoma. Based on this, a phase II trial in chordoma was recently initiated. A phase I dose-escalation study of an antibody targeting double-stranded DNA (NHS) conjugated to IL-12 is underway. The IND for this CCR co-developed agent is held by the CCR. Dr. Gulley is the coordinating PI of a phase I dose-escalation study of an anti-PDL1 antibody in patients with solid tumors. This first-in-human international study of this agent sponsored by our CRADA partner, EMD-Serono, has already enrolled and treated over 915 patients, with about 120 treated at the CCR since January 2013. Dramatic prolonged responses have been noted, including a high proportion of patients with thymic epithelial malignancies (collaboration with TGIB). This study has lead to an ongoing phase III study in lung cancer with multiple additional registration trials planned. All patients on the dose-escalation portion were enrolled at the CCR; others are being enrolled at the CCR and other centers in expansion cohorts. Collaborative Trials with Extramural Cancer Centers: A phase II study of PSA-TRICOM with GM-CSF in patients with PSA progression after local therapy for prostate cancer (Eastern Cooperative Oncology Group): recently completed and manuscript published. A phase I study of intravesical recombinant fowlpox-GM-CSF and/or recombinant fowlpox-TRICOM in patients with bladder carcinoma scheduled for cystectomy (Cancer Institute of New Jersey, CINJ): completed. A phase I study of intratumoral Panvac with GM-CSF in pancreatic cancer patients (CINJ): ongoing. A phase II study of active immunotherapy with Panvac or autologous cultured dendritic cells infected with Panvac after complete resection of hepatic metastases of colorectal carcinoma (Duke Comprehensive Cancer Center): recently published.